Redox-Tag Processes: Intramolecular Electron Transfer and Its Broad

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Redox-Tag Processes: Intramolecular Electron Transfer and Its Broad Relationship to Redox Reactions in General Yohei Okada‡ and Kazuhiro Chiba*,† †

Department of Applied Biological Science, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan ‡ Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan ABSTRACT: Explosive growth in the use of open shell reactivity, including neutral radicals and radical ions, in the field of synthetic organic chemistry has been observed in the past decade, particularly since the advent of ruthenium complexes in 2008. These complexes generally induce single-electron transfer (SET) processes via visible-light absorption. Additionally, recent significant advancements in organic electrochemistry involving SET processes to provide open shell reactivity offer a complementary method to traditional polarity-driven reactions described by two-electron transfer processes. In this Review, we highlight the importance of intramolecular SET processes in the field of synthetic organic chemistry, which seem to be more elusive than the intermolecular versions, since they are net redox-neutral and thus cannot simply be regarded as oxidations or reductions. Such intramolecular SET processes can rationally be understood in combination with concomitant bond formations and/or cleavages, and are regulated by a structural motif that we call a “redox tag.” In order to describe modern radical-driven reactions involving SET processes, we focus on a classical formalism in which electrons are treated as particles rather than waves, which offers a practical yet powerful approach to explain and/or predict synthetic outcomes.

CONTENTS 1. Introduction 1.1. Background of SET-Triggered Reactions 1.2. Why Intramolecular SET? 1.3. Redox Tag Processes 1.4. Scope of this Review 2. Early Contributions 2.1. SET-Triggered [2 + 2] Dimerization of NVinylcarbazole 2.2. SET-Triggered [2 + 2] Dimerization of transAnethole 3. Anodic SET-Triggered [2 + 2] Cycloadditions 3.1. Why Organic Electrochemistry? 3.2. Lithium Perchlorate/Nitromethane System 3.3. Anodic SET-Triggered [2 + 2] Cycloadditions Assisted by Redox Tag 3.4. Novel Reaction Design Based on Redox Tag 3.5. Mechanistic Understanding of SET-Triggered [2 + 2] Cycloadditions 3.6. Mechanistic Understanding of SET-Triggered Olefin Metathesis 3.7. Probing Intramolecular SET Processes 4. (Photo)Chemical SET-Triggered [2 + 2] Cycloadditions 4.1. Stepwise or Concerted? 4.2. Photochemical SET-Triggered [2 + 2] Cycloadditions

© XXXX American Chemical Society

4.3. Chemical SET-Triggered [2 + 2] Cycloadditions 5. (Photo)Chemical SET-Triggered Diels-Alder Reactions 5.1. Historical Background 5.2. SET-Triggered Diels−Alder Reactions of trans-Anethole 5.3. Where Is the Radical and/or Cation? 5.4. Anodic SET-Triggered Diels−Alder Reactions 5.5. Bidirectional Access to SET-Triggered Diels− Alder Reactions 6. Anodic SET Oxidations 6.1. Anodic SET-Oxidative Methoxylations 6.2. Anodic SET-Oxidative Competition Reactions 6.3. Lowering Oxidation Potentials 7. Others 7.1. Reductive SET-Triggered Reactions 7.2. Oldest and Latest; Carbazole 8. Conclusion Author Information Corresponding Author ORCID

B B B C D D D F G G H I I K M O O O

S S S T V V X Y Y Y AB AC AC AE AF AG AG AG

Special Issue: Electrochemistry: Technology, Synthesis, Energy, and Materials

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Received: July 1, 2017

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DOI: 10.1021/acs.chemrev.7b00400 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews Notes Biographies Acknowledgments References

Review

AG AG AG AG

Scheme 1. Diagram of SET Processes in Combination with Proton Transfers

1. INTRODUCTION 1.1. Background of SET-Triggered Reactions

Over the past century, the wave-particle duality of electrons has been clearly articulated both theoretically and experimentally and is now accepted curriculum in basic undergraduate quantum chemistry. Nevertheless, synthetic organic chemists are still prone to treat electrons as particles rather than waves to describe reaction mechanisms, since this classical approach is practical and powerful to explain and/or predict synthetic outcomes. Although the landscape of synthetic organic chemistry has been dominated by polarity-driven reactions involving two-electron pathways, explosive growth in the general area of radical reactivity has been witnessed in the past decade.1−12 One-electron pathways, more commonly called single electron transfer (SET) processes, must be involved in such radical-driven reactions, providing a unique open shell reactivity that offers a complementarity to traditional polarity-driven reactions. To understand such radical-driven reactions, continued attention should be paid to formal mechanisms where electrons are treated as particles, since SET processes are otherwise difficult or impossible to describe. Synthetic organic chemistry has developed in tandem with the advancement of catalysis, which can be defined as the activation of molecules for further chemical transformations that are otherwise difficult or impossible to achieve. Although transition metals and their complexes have played a central role in this field,13−20 modern synthetic organic chemists are also armed with a remarkable array of organocatalysts.21−28 Lewis acids and bases are common classes of catalysts as well,29−36 and more simply, Brønsted catalysts, in which just the action of protons is considered, are classical but still versatile catalysts in synthetic organic chemistry. Recently, Studer and Curran insightfully noted that the action of electrons can also be considered catalysis in analogy with that of protons.37 The concept of “the electron is a catalyst” also explains the term “redox catalysis.” More specifically, here, we use the term “SETtriggered reactions” to express chemical transformations caused by redox catalysis. SET processes are categorized into removal or addition of electrons from or to the molecules being studied, which can technically be regarded as one-electron oxidation or reduction. In this Review, we refer to them as oxidative and reductive SET processes (Scheme 1). Most bench-stable chemicals used as starting materials in synthetic organic chemistry are neutral closed shell species; therefore, from such neutral molecules, the removal or addition of electrons generates radical ions rather than neutral radicals. Although they might be converted into neutral radicals via further chemical reactions, most SET processes are expected to offer distinctive radical ion reactivity first, where polarity and radicals are combined in single molecules. Compared with traditional polarity-driven reactions and emerging radical-driven reactions, radical ion-driven reactions are rather elusive. However, their unique reactivity has been reviewed from various viewpoints.38−46 Because of their high reactivity, radical ions are readily trapped even by neutral nucleophiles or electrophiles to generate transient

intermediates via bond formations. It should be noted that these intermediates are still radical ions; therefore, further SET processes must be involved to complete the overall reactions. When an electron is added to radical cation intermediates or is removed from radical anion intermediates to afford neutral products, net redox-neutral processes can be achieved, illustrating that the electrons are indeed catalysts (Scheme 2). In other words, the net redox states are conserved between substrates and product. Such reactions are commonly involved in chain mechanisms, which are generally called radical ion chain processes. However, further removal or addition of electrons from or to the radical ion intermediates being studied is also common, generating simple cations or anions accompanied by appropriate proton transfers. In these cases, although the electrons are reagents rather than catalysts, we will not limit our discussion to such SET-oxidations or reductions. 1.2. Why Intramolecular SET?

Intermolecular SET processes are reasonably well understood since they can be regarded as redox processes (Scheme 3). When something is oxidized, something else must be reduced, with the electron transferred from one to the other. On the other hand, intramolecular SET processes are rather elusive since they are a net redox-neutral process and currently there are few experimental procedures suitable to detect or analyze such processes. The significant challenge in this Review is the interpretation of such intramolecular SET processes from the viewpoint of synthetic organic chemistry, more specifically, based on formal understanding of reaction mechanisms in relation to bond formation and/or cleavage. Historically, SET processes were intensively studied in the realm of photochemistry and were generally referred to as photoinduced electron transfer (PET). Although numerous photosensitizers have been devised to induce SET processes via light absorption, after the pioneering work by MacMillan47 and Yoon48 in 2008, ruthenium and iridium polypyridyl complexes have held a central place in the study of new SET-triggered reactions, which are now well-known as “photoredox B


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Scheme 2. Diagram of Net Redox-Neutral SET-Triggered Reactions

Electrons are generally treated as waves rather than particles in computational chemistry. SET processes are considered to take place between the highest occupied molecular orbital (HOMO) or lowest unoccupied molecular orbital (LUMO), namely, removal of electrons occurs from the HOMO and addition of electrons occurs to the LUMO (Scheme 1). Since both the HOMO and LUMO are usually distributed over several atoms, it can be complicated to describe SET processes, especially for intramolecular versions. Because electrons are not localized, it is virtually impossible to identify their departure and arrival points. Therefore, at first glance, there is a contradiction between the classical formalism and recent computational chemistry, which might be inevitable due to the wave-particle duality of electrons. In this context, continued and increasing attention must be given to computational approaches. However, the significant challenge of this Review is to modernize the classical formalism with particular emphasis on intramolecular SET processes.

Scheme 3. Intermolecular and Intramolecular SET Processes

catalysis.” 49−53 In addition to ruthenium and iridium polypyridyl complexes, organic chromophores, photosensitizer equivalents, have been recognized as promising options to induce SET processes via light absorption.54−60 Thus, SET processes in photochemistry are described in various ways. Here, we simply use the term “photochemical SET” in combination with “photocatalysts.” Since recent elegant reviews have given overviews of such photoredox catalysis, we have omitted their item-by-item discussion here. In this Review, reactions involving photoredox catalysis will be mentioned several times; however, we simply regard them as just one option to induce SET processes. In addition to photochemical approaches, specific chemical redox agents have been developed to induce SET processes, which will be discussed later. The third and a central aspect of this Review for the induction of SET processes are electrochemical approaches, which are described in detail in the subsequent chapter. Here, we use the terms photochemical SET (P-SET), chemical SET (C-SET), and electrochemical SET (E-SET), which are further categorized into anodic and reductive SET, to discriminate these approaches, in combination with the terms oxidative or reductive to specify the flow of electrons. Although classical formalism is still the basis of synthetic organic chemistry, a computational approach based on quantum chemistry has proven in recent years to be a powerful and irreplaceable way to understand reaction mechanisms.

1.3. Redox Tag Processes

Our basic premise is that intramolecular SET processes can be detected when they are associated with concomitant bond formations and/or cleavages, since such chemical transformations might be used as a probe. This concept has been elegantly demonstrated using a radical clock approach,61,62 enabling the study of kinetics for radical-driven reactions. We expect such chemical probes would also be a great aid to formally understand intramolecular SET processes. In this context, one of the pioneering examples was proposed by Bauld in 1983.63 He reported that chemical SET triggered the [2 + 2] dimerization of trans-anethole (1) to give the cyclobutane (2), while no corresponding cycloadduct (4) was obtained from substrate (3), which lacked an aromatic methoxy group (Scheme 4). Together with theoretical studies,64,65 he determined that the ring closure, the equivalent of cyclobutane formation, was only feasible when an “ionizable” substituent was present (Scheme 5). Namely, bond formations occurred through concomitant intramolecular SET processes (i.e., bond formation was a probe for the intramolecular SET process). Nearly two decades later, our group encountered a similar phenomenon.66 Anodic oxidative SET was found to trigger an unprecedented formal [2 + 2] cycloaddition between the enol ether (5) and terminal olefins (6), affording the cyclobutane C


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Scheme 4. SET-Triggered [2 + 2] Dimerization of transAnethole (1)

Scheme 7. Bond Formation through Concomitant Intramolecular SET Process

Scheme 8. Plausible Reaction Mechanism of the [2 + 2] Cycloaddition of the Enol Ether (5)

Scheme 5. Bond Formation through Concomitant Intramolecular SET Process

(7), while no corresponding cycloadduct (9) was obtained from the enol ether (8), which lacked an aromatic methoxy group (Scheme 6). On the basis of these observations, we Scheme 6. SET-Triggered [2 + 2] Cycloaddition between the Enol Ether (5) and Terminal Olefins (6) 1.4. Scope of this Review

From this formal understanding of intramolecular SET processes in relation to concomitant bond formations and/or cleavages, we believe that unique and novel interpretations would be given to radical-driven reactions, including wellestablished variants, leading to further reaction developments in this field. The goal of this Review is three-fold. First, we look at early contributions to SET-triggered [2 + 2] dimerizations involving radical cation chain mechanisms, with special emphasis on intramolecular SET processes. Second, we discuss intramolecular SET processes involving anodic oxidative SETtriggered [2 + 2] cycloadditions, where a redox tag definitely plays a key role. Third, we offer more generally applicable intramolecular SET processes to highlight and improve the importance of the classical formalism. Rather than conducting an exhaustive review of SET-triggered radical ion reactions, we focus instead on selected examples that feature the importance of intramolecular SET processes. We believe that a classical formalism should evolve in tandem with SET-triggered radical ion-driven reactions to advance modern synthetic organic chemistry.

assumed that intramolecular SET from an electron-rich aromatic ring to a transient cyclobutyl radical cation (7c·+) was crucial for the ring closure (Scheme 7). Formally, the aromatic ring initially functioned as an electron donor to reduce the cyclobutyl radical cation, thus generating a relatively longlived aromatic radical cation (7a·+), which then functioned as an electron acceptor to oxidize the starting enol ether (5), completing the overall reaction and also triggering the radical cation chain process (Scheme 8). Here, the aromatic ring is expected to play dual roles as both electron donor and acceptor for the bond formations, and we refer to this function as a “redox tag,” which we believe is the key to the rational design of novel radical ion-driven reactions.

2. EARLY CONTRIBUTIONS 2.1. SET-Triggered [2 + 2] Dimerization of N-Vinylcarbazole

SET processes are closely related to the generation of radical ions. We first focus on an oxidative SET-triggered [2 + 2] dimerization of N-vinylcarbazole (NVC, 10) (Scheme 9), D


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Scheme 9. SET-Triggered [2 + 2] Dimerization of NVinylcarbazole (10)

possibility of a SET-triggered reaction. However, it took a couple of decades to prove such a concept after the proposal by Woodward. The potential of radical cations as catalysts to trigger chemical transformations was initially proposed in the field of polymer chemistry. According to a comprehensive article by Plesch,69 Labes70 and Ellinger71 almost simultaneously reported that the polymerization of NVC (10) was catalyzed by various electron acceptors, but the mechanistic aspect was not fully understood at this time. In 1964, Ellinger found that cyclobutane (11), not the desired polymer, was formed under some reaction conditions.72 The reaction was further studied with Ledwith,73 who proposed the above-mentioned radical cation chain mechanism for the first time (Scheme 11).74−77

which is a pioneering example of a net-redox neutral SETtriggered reaction involving a radical cation chain mechanism. We can see the importance of intramolecular SET processes even in the earliest example in this class. Although stable radical cations, Wurster’s Red and Blue Salts, were isolated in the 19th century (Figure 1), it was not until

Scheme 11. Plausible Reaction Mechanism of the [2 + 2] Dimerization of N-Vinylcarbazole (10)

Figure 1. Structure of stable radical cations.

almost five decades later that the term “cation radical” was coined by Weitz.67 The term “radical cation” has become more prevalent in recent years. In this work, he isolated a stable radical cation of triarylamine and named it an aminium ion. As noted by Wiest,42 the concept of net redox-neutral SETtriggered reactions was first postulated by Woodward in 1942.68 He proposed that the Diels−Alder reaction could begin by intermolecular SET from the diene as an electron donor to the α,β-unsaturated carbonyl compound as an electron acceptor (Scheme 10). The thus generated radical ion pair was held Scheme 10. Proposed Mechanism of Diels-Alder Reaction (Modified)

The reaction is composed of three steps, including initiation, propagation, and termination processes, which are commonly seen in radical cation chain mechanisms. In the initiation step, a chemical oxidative SET is expected to take place from the electron-rich vinylic double bond of NVC (10) by an electron acceptor, generating the corresponding olefinic radical cation (10·+), which was then trapped by neutral NVC (10) to form the cyclobutyl framework in the propagation step. It should be noted that this formed intermediate is still a radical cation and can function as an electron acceptor to induce the next oxidative SET from the starting NVC (10), triggering the radical cation chain process. This step is also regarded as a termination step, which is the key for all net redox-neutral radical cation chain processes. The cyclobutane formation can be divided into two steps. The trapping of the radical cation of NVC (10·+) by neutral NVC (10) is expected to generate the corresponding cyclobutyl radical cation (11c·+), where the radical cation is formally localized on the cyclobutyl moiety. An intramolecular SET from the electron-rich aromatic ring to the cyclobutyl moiety

together by ionic forces to form a “dipolar aggregate,” which finally formed the neutral product by back electron transfer, which was depicted as an “irreversible rearrangement” in the original paper. He also mentioned the possibility that such a reaction could be triggered by an external donor or acceptor that did not participate in the reaction itself, indicating the E


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Scheme 12. Expected Intermolecular SET Processes

it has a high energetic barrier. This barrier could be overcome due to the presence of a large excess of methanol. It would be reasonable to expect that the equilibrium between the aromatic radical cation (11a·+) and the cyclobutyl radical cation (11c·+) was largely biased to the aromatic form. Nevertheless, if the aromatic radical cation cannot participate in further chemical transformations, the cyclobutyl radical cation could do so instead. Indeed, the carbon−carbon bond cleavage was accompanied by methoxylation, which removed the cyclobutyl radical cation (11c·+) from the equilibrium. Therefore, carbazole was clearly shown to have the potential ability to control intramolecular SET processes, which was associated with bond formations and/or cleavages. On the basis of our definition, carbazole can be regarded as the earliest example of a redox tag. This function of carbazole will be revisited in one of the latest examples as well. It should be noted that Ledwith also reported the general method80 to prepare a highly stable aminium salt, tris(p-bromophenyl)aminium hexachloroantimonate,81,82 which was an immense contribution for the further study of this class of reactions.

completes the formation of its neutral form, generating a relatively long-lived aromatic radical cation (11a·+). This process can also provide a reasonable explanation for the next step (Scheme 12). The cyclobutyl radical cation (11c·+) can be regarded as the radical cation equivalent of starting NVC (10·+). Therefore, it is reasonable to expect that redox potentials of these molecules are similar. Intermolecular SET from neutral NVC (10) to the cyclobutyl radical cation (11c·+) seems possible, but it might be reversible and undesired back electron transfer should also be considered. On the other hand, the aromatic radical cation (11a·+) is expected to have a higher redox potential than that of the radical cation starting NVC (10·+). In such a situation, intermolecular SET from neutral NVC (10) to the aromatic radical cation (11a·+) enjoys an energetic advantage and thus takes place effectively. Unfortunately, the scope of the reaction is limited to NVC (10), and even other vinylamines were found to be unsuccessful. Nevertheless, the [2 + 2] dimerization of NVC (10) is indeed a pioneering net redox-neutral SET-triggered reaction involving a radical cation chain mechanism. Additionally and more importantly for this Review, Ledwith reported the SET-triggered ring-opening reaction of the cyclobutane (11) (Scheme 13).78,79 Chemical oxidative SET

2.2. SET-Triggered [2 + 2] Dimerization of trans-Anethole

Several net redox-neutral SET-triggered Diels−Alder reactions involving radical cation chain mechanisms have also been developed, including the [4 + 2] dimerization of 1,3cyclohexadiene (CHD, 13) as a prototypical example (Scheme 15). The early examples of this class of reactions were mainly triggered by photochemical SET processes to afford the dimer of CHD (14). In this context, in 1981, Bauld reported a radical cation Diels−Alder reaction triggered by chemical SET using an aminium salt.83 The transformation itself had been reported previously; however, the importance of this work was the use of a bench stable aminium salt to trigger the reaction, leading to significant enhancement of its scope and synthetic utility. He studied radical cation Diels−Alder reactions systematically and intensively,84,85 paving the way for further net redox-neutral SET-triggered reactions involving radical cation chain mechanisms. Here we paid special attention to the [2 + 2] dimerization of trans-anethole (1) (Scheme 4). Bauld studied the [2 + 2] dimerization both experimentally and theoretically. In analogy with the [2 + 2] dimerization of NVC (10), in the initiation step, chemical oxidative SET from the electron-rich styrenic double bond of trans-anethole (1) to an electron acceptor gave the corresponding olefinic radical cation (1·+), which was then trapped by neutral trans-anethole (1) to form

Scheme 13. SET-Triggered Ring Opening Reaction of the Cyclobutane (11)

was found to induce the carbon−carbon bond cleavage of the cyclobutane, which was accompanied by trapping with methanol to give the methoxylated product (12). Since carbazole is readily oxidized, an oxidative SET should take place from the aromatic ring (Scheme 14). However, subsequent carbon−carbon bond cleavage, accompanied by carbon−oxygen bond formations, occurred at the cyclobutyl moiety. This observation unambiguously indicated that the aromatic radical cation (11a·+) and the cyclobutyl radical cation (11c·+) were in equilibrium. Intramolecular SET from the aromatic ring to the cyclobutyl moiety is also possible, although F


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Scheme 14. Plausible Reaction Mechanism of the Ring Opening Reaction of the Cyclobutane (11)

Scheme 15. SET-Triggered [4 + 2] Dimerization of 1,3Cyclohexadiene (13)

Scheme 16. Plausible Reaction Mechanism of the [2 + 2] Dimerization of trans-Anethole (1)

the cyclobutyl framework in the propagation step (Scheme 16). He proposed that the cyclobutyl framework was incomplete and possessed a “long bond,” also referred to as a “one electron bond,” which was first postulated by Pauling in 1931.86 Bauld pointed out that the completion of the cyclobutane formation was only feasible when an ionizable substituent was present. Namely, intramolecular SET from the ionizable methoxyphenyl ring to the cyclobutyl radical cation was crucial to afford the neutral complete form. The generated relatively long-lived aromatic radical cation was then reduced by the starting transanethole (1), triggering the radical cation chain process. He also mentioned that no corresponding cycloadduct (4) was obtained from the substrate without the aromatic methoxy group (3), suggesting that the strength of the aromatic electron donor strongly depends on its electron density. Additionally, again in analogy with the NVC cyclobutane (11), a ring opening reaction was possible for the anethole cyclobutane (2) (Scheme 17). In this case, the stereochemical outcome was the probe for the ring-opening reaction, namely, the isomerization from the syn to anti form was observed under the chemical oxidative SET conditions. Since the methoxyphenyl ring was readily ionizable, the SET from the anethole cycloadduct (2) was expected to take place on the aromatic ring (Scheme 18). However, subsequent carbon−carbon bond cleavage occurred at the cyclobutyl moiety, suggesting that an intramolecular SET from the aromatic ring to the cyclobutyl moiety was possible. In other words, the aromatic radical cation

(2a·+) and cyclobutyl radical cation (2c·+) were in equilibrium. Therefore, in addition to carbazole, the methoxyphenyl ring was also shown to have the potential ability to control intramolecular SET processes, which are associated with bond formations and/or cleavages. The methoxyphenyl ring can be regarded as an example of a redox tag based on our definition, which was revisited by our group almost two decades later.

3. ANODIC SET-TRIGGERED [2 + 2] CYCLOADDITIONS 3.1. Why Organic Electrochemistry?

Arguably, electrodes are the greenest redox agents and processes in which the only net agent is the electron itself are possible. The use of electrode processes in synthetic organic chemistry is variously referred to as organic electrochemistry, electroorganic chemistry, or electrosynthesis. These terms are equivalent, and here we use the term organic electrochemistry. Oxidative SET takes place at the anode, while a concomitant reductive SET takes place at the cathode. These SET processes G


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Scheme 17. SET-Triggered Ring Opening Reaction of the Cyclobutane (2)

Scheme 18. Plausible Reaction Mechanism of the Ring Opening Reaction of the Cyclobutane (2)

which are recently referred to as “naked” lithium cations.97 The unique catalysis offered by naked lithium has been employed to promote not only Diels−Alder reactions but a wide variety of chemical transformations.98−103 In 1994, our group found that the ability of the lithium cation to accelerate Diels−Alder reactions was much improved when dissolved in nitromethane (NM), and a LPC/NM system was used as an electrolyte solution for synthetic organic electrochemistry. The first example was the Diels−Alder reactions of unstable quinones (16), which were generated in situ by anodic SET-oxidation of the corresponding hydroquinones (15) (Scheme 19).104 In this

are generally called anodic oxidation and cathodic reduction, respectively, regardless of the redox states in the final products. Thus, an “anodic oxidation-triggered redox neutral process” is also be possible. The equipment required for organic electrochemistry, such as potentio/galvanostats, divided/ undivided cells, and electrodes, is not commonly found in synthetic organic chemistry laboratories; however, they provide effective reaction variables that can dramatically alter the reaction progress. For example, a synthetic outcome could be modified by just changing the electrode materials. Furthermore, and perhaps most importantly, the redox strength is switchable in a facile and precise manner by varying the potential applied. In photochemical or chemical SET, there is a need for the selection of suitable chemical redox agents since no SET process is expected when the redox strength is lower than the redox potentials of the molecules being studied. On the other hand, electrodes can have arbitrary redox strengths, as long as they are maintained in the potential window of the solvents used, enabling oxidative and reductive SET of any organic compound. It should also be noted that electron equivalents used for electrochemical SET processes can be simply monitored as the amount of electricity passed in real time, which is generally expressed in units of Faradays per mole (F/ mol). The reactions can be quenched directly by just switching off the electrical potential or current; therefore, no complex workup procedures are required. Since comprehensive reviews have already been conducted of organic electrochemistry,87−94 we have omitted their item-by-item discussion in this Review.

Scheme 19. SET-Triggered Diels-Alder Reactions in Lithium Perchlorate/Nitromethane System

case, the process required both anodic oxidative SET and deprotonation, generating neutral but highly reactive quinones, which were then trapped by dienes (17) to give the cyclohexenes (18). Here, electrons are reagents rather than catalysts and the overall process is not net redox-neutral, but rather oxidation. Thereafter, our reaction development was governed by the use of the LPC/NM system as an electrolyte solution, including [4 + 2] cycloadditions,105−112 [3 + 2] cycloadditions,113−117 and N-α functionalizations of pyrrolidine derivatives.118−122 It should be noted that all of these examples

3.2. Lithium Perchlorate/Nitromethane System

In 1990, Grieco reported that a high concentration of lithium perchlorate (LPC) in diethyl ether significantly accelerated Diels−Alder reactions.95 Although the acceleration was attributed to “internal pressure” in the original paper, Dailey proposed that it could be explained by the unique Lewis acidity of weakly- or noncoordinated lithium cations in solution,96 H


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methoxy group (8) to give the olefin (19) (Scheme 20).124 Deuterium labeling experiments clearly revealed that the source

require double anodic oxidative SET and deprotonation, and thus are categorized into polarity-driven reactions. We also investigated the fundamental role of the LPC/NM system by using 7Li NMR analysis and calorimetric studies to reveal that an entropic effect was important to enable unprecedented net redox-neutral formal [2 + 2] cycloadditions triggered by anodic oxidative SET processes, which will be discussed in detail in the following section.123

Scheme 20. SET-Triggered Olefin Metathesis of the Enol Ether (8)

3.3. Anodic SET-Triggered [2 + 2] Cycloadditions Assisted by Redox Tag

In 2001, we discovered that anodic oxidative SET with assistance of the LPC/NM system could trigger unprecedented formal [2 + 2] cycloadditions between the enol ether (5) and terminal olefin (6), affording the cyclobutane (7), while no corresponding cycloadduct (9) was obtained from the enol ether without the aromatic methoxy group (8) (Scheme 6).66 Initial anodic oxidative SET was expected to take place at the readily oxidizable enol ether moiety to generate the corresponding radical cation (5·+), which was then trapped by terminal olefins (6). Due to the short lifetime of the enol ether radical cation (5·+), a large excess of terminal olefins (6) was essential for successful reaction (Scheme 8). In these cases, even unactivated olefins could function as effective carbon nucleophiles, presumably assisted by the unique properties of the LPC/NM system. The generated transient cyclobutyl radical cation (7c·+) was then reduced by intramolecular SET from the methoxyphenyl ring to give the relatively long-lived aromatic radical cation (7a·+), which finally oxidized the starting enol ether (5) to complete the overall net redox-neutral process and trigger the radical cation chain mechanism. The fact that the reaction was complete using 0.5 F/mol of electricity, a catalytic amount, clearly suggested the involvement of a radical cation chain mechanism. The aromatic ring is expected to have dual functions, electron donor and acceptor (i.e., a redox tag). In analogy with the [2 + 2] dimerization of trans-anethole (1), there must be strict limits for the electron density of the aromatic ring to function as a redox tag, since the enol ether with nonsubstituted phenyl ring (8) was an entirely unsuccessful substrate for the reaction. The enol ether (5) indeed has lower oxidation potential than the enol ether without an aromatic methoxy group (8) but only by 0.04 V vs Ag/AgCl (Figure 2). This suggests that the anodic

of the methylene group was the terminal olefin. Therefore, we concluded that anodic oxidative SET was possible even for the enol ether without an aromatic methoxy group (8) to generate the corresponding radical cation (8·+), and its trapping by terminal olefins (6) also occurred to form transient cyclobutyl radical cation (9c·+) (Scheme 21). The ring closure was only Scheme 21. Plausible Reaction Mechanism of the Olefin Metathesis

feasible when an aromatic redox tag was present; therefore, the cyclobutyl radical cation (9c·+) must be decomposed. There are two possible routes to cleave the cyclobutyl moiety. One gives the starting combination, the enol ether radical cation (8·+) and terminal olefins (6), while the other eventually affords the desired synthetic outcome via olefin metathesis. These observations confirmed that an intramolecular SET process regulated by a redox tag was the key for the net redox-neutral [2 + 2] cycloaddition involving a radical cation chain process.

Figure 2. Oxidation potential (vs Ag/AgCl) of the enol ethers (5, 8).

3.4. Novel Reaction Design Based on Redox Tag

oxidative SET for an enol ether without an aromatic methoxy group (8) is slightly more difficult than that of the enol ether with an aromatic methoxy group (5). However, the redox strength is switchable in organic electrochemistry, and the potential can be adjusted to a value to induce anodic oxidative SET even from the enol ether without an aromatic methoxy group (8). Indeed, electrical current was observed during the reaction. This was unambiguous evidence that the anodic oxidative SET process involved oxidation and reduction at the anode and cathode. Through careful investigations, we discovered that olefin metathesis took place instead of a formal [2 + 2] cycloaddition for the enol ether without an aromatic

On the basis of these findings, we questioned whether a rational design for novel reactions would be possible. We extracted the structural motifs required for the anodic oxidative SETtriggered [2 + 2] cycloadditions (i.e., a readily oxidizable enol ether moiety and an aromatic redox tag, more specifically, an alkoxyphenyl ring). With this hypothesis, we then prepared the novel enol ether (20), where one oxygen atom was expected to have dual roles as an enol ether and an alkoxyphenyl ring (Figure 3). When enol ether (20) was used instead of enol ether (5), the results were better than expected in that the corresponding [2 + 2] cycloadduct (21) was obtained in I


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present in the intermediate. There is no requirement for its origin from the starting substrates. Therefore, we designed a combination using a terminal olefin with a redox tag, allylanisole (22), and an aliphatic enol ether (23) (Figure 4).

Figure 3. Toward novel reaction design based on redox tag.

excellent yield, confirming that our reaction design was feasible (Scheme 22).125−128 The reaction mechanism was understood Scheme 22. SET-Triggered [2 + 2] Cycloaddition between the Enol Ether (20) and Terminal Olefins (6)

Figure 4. Toward novel reaction design based on redox tag.

The initial anodic oxidative SET was expected to take place from the enol ether (23), and if thus generated radical cation (23·+) was trapped by the terminal olefin, the intermediate with a redox tag would form. To our delight, the reaction proceeded smoothly by a radical cation chain process, as evidenced by the fact that the reaction was complete with 0.5 F/mol, a catalytic amount of electricity, to give the cyclobutane (24) (Scheme 24).129,130 We also found that the cyclic enol ether,

in analogy with the reaction of enol ether (5), in that the initial anodic oxidative SET occurred from the electron-rich enol ether moiety to generate the corresponding radical cation (20·+), which was then trapped by terminal olefin (6) (Scheme 23). An intramolecular SET from the aromatic ring to the

Scheme 24. SET-Triggered [2 + 2] Cycloaddition between Allylanisole (22) and the Enol Ethers (23, 25)

Scheme 23. Plausible Reaction Mechanism of the [2 + 2] Cycloaddition of the Enol Ether (20)

dihydropyran (25), gave the cyclobutane (26) with a simpler stereochemical outcome (Scheme 25). The olefin without an aromatic methoxy group, allylbenzene (27), did not give the corresponding [2 + 2] cycloadduct (28) at all, clearly suggesting the essential role of the redox tag to regulate the intramolecular SET process to complete the formation of the cyclobutane ring (Scheme 26). Even in the presence of a large excess of anisole (29), allylbenzene (27) was not entirely effective for the anodic oxidative SET-triggered formal [2 + 2] cycloaddition. As discussed later, olefin metathesis was also observed with this combination, namely, an olefin without a redox tag and an aliphatic linear enol ether (Scheme 34). Therefore, nucleophilic trapping of the enol ether radical cation by the olefin must be possible even without the redox tag. In other words, the formation of the cyclobutyl radical cation was definitely triggered by the anodic oxidative SET process (Scheme 35). Taken all together, this clearly suggested that an intramolecular SET process was indeed crucial to complete the formation of a cyclobutane ring, and the intermolecular SET process was not an alternative (Scheme 27). This could be due to the extremely short lifetime of the transient cyclobutyl

cyclobutyl radical cation (21c·+) completed its formation and thus generated the relatively long-lived aromatic radical cation (21a·+), which was reduced by the starting enol ether (20). The involvement of the radical cation chain process was again confirmed by the fact that the reaction was completed with 0.5 F/mol, a catalytic amount of electricity. With this successful trial in hand, we then turned our attention to modifying the combination of structural motifs required for the reaction. The formation of a neutral cyclobutane is only feasible when an aromatic redox tag is J


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additional methylene groups, distancing the electron donor and acceptor. When the reactions of these olefins (30, 31) were carried out with dihydropyran (25), both olefins were found to be effective for the anodic oxidative SET-triggered formal [2 + 2] cycloadditions to give the desired cyclobutanes (32, 33) in excellent yields, respectively (Scheme 28).131 These results

Scheme 25. Plausible Reaction Mechanism of the [2 + 2] Cycloaddition of Allylanisole (22)

Scheme 28. SET-Triggered [2 + 2] Cycloadditions of Dihydropyran (25)

Scheme 26. Unsuccessful SET-Triggered [2 + 2] Cycloadditions of Allylbenzene (27)

were, at first glance, not surprising, since the linkers are not rigid and thus electron donor and acceptor can come into close proximity under the reaction conditions. However, this assumption will be tested, as discussed later. Since we only had demonstrated the ability of the methoxy phenyl ring to function as an aromatic redox tag, we then focused on whether tuning the electron density of the aromatic ring would be possible. Therefore, a series of allylarenes was prepared and tested for anodic oxidative SET-triggered formal [2 + 2] cycloadditions with dihydropyran (25) as a model. When the oxygen atom of the aromatic methoxy group was switched to nitrogen (34) or sulfur (35), the desired cyclobutanes were not obtained at all (Scheme 29). These results were disappointing; however, it was reasonably understood that they were too readily oxidized, making selective SET of dihydropyran impossible. This explanation was further confirmed by the fact that an additional methoxy

radical cation, which must be reduced immediately by a rapid intramolecular SET process. Scheme 27. Effectivity of SET Processes over Cyclobutane Formations

Scheme 29. Unsuccessful SET-Triggered [2 + 2] Cycloadditions of Dihydropyran (25)

3.5. Mechanistic Understanding of SET-Triggered [2 + 2] Cycloadditions

It is reasonable to believe that the linker structure tethering the electron donor and acceptor would have a significant impact on the intramolecular SET process. In order to study such an impact over the anodic oxidative SET-triggered [2 + 2] cycloadditions, we designed and prepared two other olefins, both with an aromatic redox tag (30, 31). Compared with allylanisole (22), the olefinic double bonds were separated by K


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We also carefully investigated the anodic oxidative SETtriggered reaction of the obtained cyclobutane (26, 41) in order to verify the reversibility of intramolecular SET processes (Scheme 31). The initial anodic oxidative SET was expected to

group (36, 37) was disadvantageous for the reaction, since the resulting oxidation potential was lower than that of dihydropyran (25). On the other hand, a weakly electrondonating methyl group was found to be an effective tuning motif. The oxidation potentials of the allylarenes were reasonably decreased in relation with the number of methyl groups (38−40) (Scheme 30). Gratifyingly, this tendency was

Scheme 31. SET-Triggered Cycloreversions of the Cyclobutane (26, 41)

Scheme 30. SET-Triggered [2 + 2] Cycloadditions of Allyarenes with Oxidation Potential (vs Ag/AgCl)

take place from the readily oxidizable electron-rich aromatic ring to generate a relatively long-lived aromatic radical cation. In analogy to the ring opening of the NVC cyclobutane (11) and the anethole cyclobutane (2), we expected that cycloreversion would be possible if the intramolecular SET between the aromatic ring and cyclobutane moiety was reversible. Although the yield was low and does not have synthetic utility, a redox tag indeed had the potential to induce cycloreversion of the cyclobutane, affording the starting allylanisole. In addition to the cycloreversion, isomerization from the trans to cis form was also observed, which was a clear probe for the ring-opening reaction. These results unambiguously showed that the aromatic radical cation and the cyclobutyl radical cation were in equilibrium and could be interconverted via a rapid intramolecular SET process (Scheme 32). In contrast to the [2 + 2] cycloadditions, the cycloreversion required a large excess of electricity, suggesting that a radical cation chain mechanism was not involved. The enol ether radical cation (25·+) should be released simultaneously when allylanisole (22) is afforded from the cyclobutane (26), although its direct detection is challenging. In order to trap the released enol ether radical cation (25·+), the anodic oxidative SET-triggered cycloreversion was carried out in the presence of another olefin with a redox tag (30) (Scheme 33). Although it seemed that the radical cation chain process was not involved, the crossover formal [2 + 2] cycloaddition was indeed possible to unambiguously confirm that the enol ether radical cation (25·+) was released during the cycloreversion. These observations suggested that intermolecular SET was indeed reversible, and the aromatic radical cation and cyclobutyl radical cation were in biased equilibrium. While the aromatic radical cation is expected to be highly favored, it is not able to participate in further chemical transformations. On the other hand, although the cyclobutyl radical cation is expected to contribute poorly to the equilibrium, it can participate in further chemical transformation ( i.e., cycloreversion), which removes the cyclobutyl radical cation from the equilibrium. Taken together, the reaction mechanisms of both [2 + 2] cycloaddition and cycloreversion were rationally explained by intramolecular SET regulated by a redox tag. We can now propose the reaction mechanism of the anodic oxidative SET-triggered cycloreversion of the cyclobutane (26), which is clearly understood as a redox tag-regulated intramolecular SET process. The initial anodic oxidative SET is expected to occur at the redox tag to generate the relatively

also related to the ability to function as a redox tag, namely, the yield of the corresponding [2 + 2] cycloadducts increased in accordance with the oxidation potentials. A simple rule for the aromatic ring to function as an effective redox tag has emerged, namely, the lower the oxidation potential the better, as long as it is kept higher than that of dihydropyran (25) to ensure its selective anodic oxidative SET even in the presence of a large excess of allylarenes. Redox tags should play roles as both reducing and oxidizing agents throughout the reaction process; therefore, it is logical that the oxidation potential must be balanced. For the reducing function, a lower oxidation potential would be better, whereas a higher oxidation potential would be preferred for the oxidizing function, which is the key for the radical cation chain process. L


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Scheme 32. Plausible Reaction Mechanism of the Cycloreversion of the Cyclobutane (26)

Scheme 33. SET-Triggered Crossover [2 + 2] Cycloaddition

Scheme 34. SET-Triggered [2 + 2] Cycloaddition and Olefin Metathesis of the Enol Ether (42)

long-lived aromatic radical cation (26a·+), which is in equilibrium with the cyclobutyl radical cation (26c·+) via a rapid reversible intramolecular SET process. There are two possibilities for the generated transient and disfavored cyclobutyl radical cation (26c·+). First, it can participate in a ring opening reaction, with cleavage of one carbon−carbon bond, resulting in isomerization from the trans to the cis form through the reconstruction of this bond. Second, it can also participate in cycloreversion, with cleavages of two carbon− carbon bonds, to afford allylanisole (22) with simultaneous release of the enol ether radical cation (25·+), which could be detected after trapping by another olefin with a redox tag (30). Unfortunately, we are still far from a complete picture of the anodic oxidative SET-triggered olefin metathesis, which would also be a useful probe to understand intramolecular SET processes. Therefore, we revisited the anodic oxidative SETtriggered olefin metathesis to elucidate the complete reaction mechanism.

simultaneous release of the enol ether radical cation (8·+), but it was still elusive. Through careful monitoring of the reaction, we observed the formations of the enol ether (8) and phenylpropionaldehyde (48). The possibility that the transient cyclobutyl radical cation (47c·+) was cleaved into an olefinic radical cation (44·+) and neutral enol ether (8) cannot entirely be ruled out. However, it seems more reasonable that the cleavage afforded a neutral olefin (44), olefin metathesis product, and enol ether radical cation (8·+). Therefore, it was indirectly confirmed that the generated enol ether radical cation (8·+) can also be reduced to the neutral form under the reaction conditions. We also tested the anodic oxidative SETtriggered reaction of the enol ether (8) in the absence of olefin and observed the formation of phenylpropionaldehyde (48) (Scheme 36). This is a unique demonstration of the distinctive reactivity of radical cation species, since the usual acidic hydrolysis of the enol ether gives phenylbutyraldehyde (49) instead of phenylpropionaldehyde (48). With these observations in hand, we now can detail the entire reaction mechanism of the anodic oxidative SET-triggered metathesis. The enol ether radical cation is initially trapped by the olefin without a redox tag to generate a transient cyclobutyl radical cation. Since the redox tag is not present, the cyclobutyl radical cation must be decomposed into neutral olefin, metathesis product, and the enol ether radical cation. There are two possibilities for the

3.6. Mechanistic Understanding of SET-Triggered Olefin Metathesis

We prepared an aliphatic enol ether (42) and tested it as a model in the reaction.132 As expected, the enol ether (42) was effectively trapped by an olefin with a redox tag, allylanisole (22), under the anodic oxidative SET conditions to give the cyclobutane (43), while the reaction with an olefin without an aromatic methoxy group, allylbenzene (27), gave the olefin methathesis product (44) (Scheme 34). We found that the olefin with a cyclohexyl ring (45) or a slightly remote phenyl ring from the olefinic double bond, phenylbutene (46), gave better yields for the reaction. When the enol ether radical cation (42·+) was trapped by phenylbutene (46), the generation of a cyclobutyl radical cation (47c·+) was expected, which was then cleaved into the olefin metathesis product (44) (Scheme 35). This cleavage should be associated with M


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Scheme 35. Plausible Reaction Mechanism of the Olefin Metathesis of the Enol Ether (42)

desired cyclobutanes (50, 51) but also olefin metathesis products (44) were observed (Scheme 37). It should be noted that this was not the case for the reaction with allylanisole. We initially assumed that even though an electron donor and acceptor are tethered by elongated alkyl chains, the linkers are not rigid and therefore have only little impact over intramolecular SET processes since they can come in close proximity under the reaction conditions. However, the results herein unambiguously suggest that the linker structures tethering the electron donor and acceptor, even freely rotatable alkyl chains, have a significant impact over intramolecular SET processes. There are two potential pathways for the intramolecular SET process, namely, through bond and though space. The linker structures may have little impact over intramolecular SET through space; however, they do have a significant impact over through bond versions. In order to understand these potential pathways for intramolecular SET in detail, further experimental and theoretical studies are needed.

Scheme 36. SET-Triggered and Acidic Hydrolysis of the Enol Ether (8)

released enol ether radical cation, namely, reduction to afford a neutral enol ether and oxidative hydrolysis to give phenylpropionaldehyde. The anodic oxidative SET-triggered metathesis has also proven to be a powerful probe to understand intramolecular SET events. When the anodic oxidative SET-triggered [2 + 2] cycloadditions of the linear aliphatic enol ether (42) were carried out in the presence of olefins (30, 31), not only the

Scheme 37. SET-Triggered [2 + 2] Cycloadditions and Olefin Metathesis of the Enol Ether (42)

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3.7. Probing Intramolecular SET Processes

radical cation could be reduced by the second aromatic ring, and then further reduced by the “second” enol ether via formal stepwise intramolecular SET, which regenerates the enol ether radical cation that can potentially to be trapped by the olefin as well. The third possibility leads to the formation of biscyclobutane (54). If these scenarios are all in play, the ratio between mono- and bis-cyclobutane will reflect the effectiveness of the various intramolecular SET processes. The possibility of simultaneous dual anodic oxidative SET to generate two distonic enol ether radical cations cannot entirely be ruled out; however, it seems reasonable to regard it as remote. A dramatic difference was observed when linkers composed of three carbons, namely, propylene (56) and dimethylmethylene (57), were used to tether the two enol ethers (Scheme 40). The bis-enol ether tethered via a propylene linker (56) gave the monocyclobutane (58) selectively in the early stage of the reaction, while bis-cyclobutane (59) was mainly obtained in the later stage. This observation clearly suggested that the intramolecular SET process was not effective over the propylene linker, and thus, the aromatic radical cation was reduced via an intermolecular SET process (Scheme 41). In sharp contrast, bis-cyclobutane (61) was selectively formed even in the early stage of the reaction when the bis-enol ether tethered by a dimethylmethylene linker (57) was used and only slight amount of monocyclobutane (60) was obtained, indicating that the intramolecular SET process was much more effective over the dimethylmethylene linker. It seems reasonable that the two enol ethers were able to come in close proximity when they were tethered by a freely rotatable propylene linker rather than by a somewhat rigid dimethylmethylene linker. However, intramolecular SET over the propylene linker was found to be less effective than that over the dimethylmethylene linker. This may indicate that the contribution of intramolecular SET through bond was more significant than that through space for these reactions. Here, we clearly demonstrated that the bis-enol ether was a powerful probe to study intramolecular SET processes.

In order to further study the impact of linker structures on intramolecular SET processes, we prepared a series of bis-enol ethers (52), where two enol ethers were tethered through several alkyl linkers.133 The bis-enol ethers (52) were designed to form mono- (53) or bis-cyclobutane (54) under the reaction conditions, which would be indicative of the efficacy of the intramolecular SET processes (Figure 5). The initial anodic

Figure 5. Structure of the bis-enol ether (52), mono-cyclobutane (53), and bis-cyclobutane (54).

oxidative SET is expected to take place from one enol ether moiety, generating the corresponding radical cation (52·+), which is then trapped by the olefin (55) (Scheme 38). The formed transient cyclobutyl radical cation (53c·+) is then reduced to its neutral form via rapid intramolecular SET from the aromatic ring, generating the relatively long-lived aromatic radical cation (53a·+). At this stage, one can expect three possible outcomes for the aromatic radical cation (Scheme 39). First, it could be reduced by the starting bis-enol ether via intermolecular SET, completing the overall reaction and triggering the radical cation chain mechanism, leading to the formation of monocyclobutane (53). Second, the aromatic radical cation could be reduced by the “second” aromatic ring via intramolecular SET and then further reduced by the starting bis-enol ether via intermolecular SET, leading to the same synthetic outcome as the first possibility. Third, the aromatic

4. (PHOTO)CHEMICAL SET-TRIGGERED [2 + 2] CYCLOADDITIONS 4.1. Stepwise or Concerted?

As mentioned in the introduction, explosive growth in the general area of radical reactivity has been observed over the past decade, generally involving photochemical, chemical, or

Scheme 38. Expected Reaction Mechanism of [2 + 2] Cycloaddition of the Bis-Enol Ethers (52)

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Scheme 39. Expected Reaction Mechanism of [2 + 2] Cycloaddition of the Bis-Enol Ethers (52)

(1) proceeds via a concerted or stepwise fashion. Next, we discuss modern SET-triggered reactions of trans-anethole (1), with special emphasis on intramolecular SET processes. Since Bauld’s first report in 1983, the [2 + 2] dimerization of trans-anethole (1) has been a useful model to investigate the mechanism of SET-triggered reactions. A similar [2 + 2] dimerization of methoxystyrene (62), affording the cyclobutane (63), was also reported by Tokumaru in 1981 (Scheme 42),134 and we include this reaction as well in our mechanistic discussions. Surprisingly, no corresponding [2 + 2] dimerization of the substrate without an aromatic methoxy group (3) has been reported so far, and the number of examples for the reaction of styrene without the aromatic methoxy group (64) is also very limited.135−137 As clearly pointed out by Bauld, this indicates that the formation of cyclobutane is not feasible unless an ionizable substituent is present (i.e., a redox tag). It is widely accepted that the stereochemical outcome would be a clear probe to determine whether the cycloaddition mechanism proceeds via a concerted or stepwise fashion. The concerted formation would give a cycloadduct with the stereochemistry of the starting substrate conserved, while a diastereomixture would be produced by the stepwise mode. This simple rule can be applied to the [2 + 2] dimerization of trans-anethole (1) but is not the case for the [2 + 2] dimerization of methoxystyrene (62). However, since isomerization between trans and cis forms is also possible for starting anethole, the interpretation of the stereochemical outcome can

Scheme 40. SET-Triggered [2 + 2] Cycloadditions of the Bis-Enol Ethers (56, 57)

electrochemical SET processes. In this chapter, we attempt to provide generality as to how the redox tag concept can be applied to explain and understand the reaction mechanisms, by using selected recent examples. Initially, we revisit the open question of whether the [2 + 2] dimerization of trans-anethole P


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Scheme 41. Effectivity of SET Processes over Cyclobutane Formations

4.2. Photochemical SET-Triggered [2 + 2] Cycloadditions

Scheme 42. SET-Triggered [2 + 2] Dimerization of Methoxystyrene (62)

Photoredox catalysis has greatly expanded the utility of the above-mentioned [2 + 2] dimerizations to construct cyclobutyl frameworks. Recent advancement of reactions in this class has been comprehensively reviewed by Bach.147 Currently, not only anethole (1) and methoxystyrene (62) but also their various derivatives can participate in the reactions. In 2010, Yoon demonstrated intramolecular [2 + 2] cycloadditions that were rationally designed on the basis of early examples.148 Namely, anethole and styrene moieties were tethered by various linkers and tested as substrates for the intramolecular [2 + 2] cycloaddition. For example, the photochemical SET-Triggered [2 + 2] cycloaddition of the bis-styrene (64) gave the cyclobutane (65) (Scheme 43). This is one of the earliest examples that took advantage of photochemical oxidative SET

be complicated. At first glance, the SET-triggered [2 + 2] dimerizations should proceed in a stepwise fashion, involving at least a SET process and bond formation, as also assumed by Ledwith. In the original paper, based on stereochemical observations, Bauld concluded that the [2 + 2] dimerization of anethole was inherently stereospecific and they proposed a unique mechanism via an intermediate with a long bond, as mentioned above.63 This mechanistic discussion has been revisited several times, for example by Lewis,138 Takamuku,139 Chow,140 and Brede.141 The [2 + 2] dimerization of methoxystyrene (62) has also been under much mechanistic discussion and was reviewed by Wiest in combination with their own theoretical studies.142 This open question was resolved by the use of a clever mass spectrometry technique143−145 by Metzger in 2008.146 Extractive electrospray ionization enabled the detection of two different transient radical cation intermediates, namely, the cyclobutyl radical cation (2c·+) and the aromatic radical cation (2a·+), which showed specific fragmentation patterns in mass spectroscopy. Thus, it was concluded that the [2 + 2] dimerization of anethole (1) and methoxystyrene (62) proceeded in a stepwise fashion.

Scheme 43. SET-Triggered [2 + 2] Cycloadditions of BisStyrenes (64, 66)

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processes, whereas most photoredox catalysis has focused on the use of photochemical reductive versions, generating radical anions. The photochemical oxidative SET was expected to take place from the more easily oxidized anethole double bond rather than the unsubstituted styrene one to generate the corresponding olefinic radical cation (64·+), which was then trapped by the styrene double bond to form the cyclobutyl framework (Scheme 44). No corresponding cyclobutane (67)

Scheme 45. Expected Reaction Mechanism of the [2 + 2] Cycloaddition of the Bis-Styrene (66)

Scheme 44. Plausible Reaction Mechanism of the [2 + 2] Cycloaddition of the Bis-Styrene (64)

Scheme 46. SET-Triggered [2 + 2] Dimerization of transAnethole (1) and the Cycloreversion of the Cyclobutane (2)

was obtained from a substrate lacking an aromatic methoxy group (66), which was in accord with Bauld’s and our observations. The redox strength of the ruthenium photocatalysts used was not sufficient to induce a photochemical oxidative SET from the substrate without the aromatic methoxy group (66). It could also be hypothesized that the desired cycloadduct was hardly obtained even though initial oxidative SET was possible, since intramolecular SET from the aromatic ring to the cyclobutyl radical cation might not be efficient (Scheme 45). Yoon also rationally demonstrated the intermolecular [2 + 2] cycloadditions of anethole and its derivatives and clearly confirmed the reversibility of the reaction, namely, that cycloreversion was possible (Scheme 46).149 The photochemical oxidative SET from the cyclobutane (2) generated the starting anethole (1), and the cycloreversion was further confirmed by the crossover Diels−Alder reaction using isoprene (68), affording the cyclohexene (69) (Scheme 47), which will be discussed later. Thus, the aromatic radical cation and cyclobutyl radical cation were in equilibrium (Scheme 48). The initial photochemical oxidative SET was expected to generate the aromatic radical cation (2a·+), which was potentially converted into the cyclobutyl radical cation (2c·+) via a reversible intramolecular SET process. In these cases, the reaction mechanisms are rationally understood and explained based on the redox tag concept, which regulated the intramolecular SET processes throughout the overall reaction.

Scheme 47. SET-Triggered Crossover Diels-Alder Reaction

Nicewicz showed the power of organic photoredox catalysis using the [2 + 2] dimerizations of anethole (1) and its derivatives.150 Nicewicz mentioned that such SET-triggered [2 + 2] dimerizations are hampered by three competing pathways, including isomerization of starting olefins, back electron transfer, and cycloreversion. Nicewicz developed a creative combination to realize metal-free organic photochemical oxidative SET-triggered [2 + 2] dimerization of anethole derivatives. They used pyrylium salts as photocatalysts in combination with simple arenes, such as anthracene or naphthalene, which they called electron relay additives. These additives were expected to be involved in mediated SET processes, which were also widely employed in organic electrochemistry. The use of creative redox mediators in the field of synthetic organic chemistry has been comprehensively reviewed by Little.89 R


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Scheme 49. Successful and Unsuccessful SET-Triggered [2 + 2] Dimerization of Styrenes

4.3. Chemical SET-Triggered [2 + 2] Cycloadditions

leading to new reaction developments in combination with existing catalysis.

Hypervalent iodine reagents have found significant applications in the field of synthetic organic chemistry.151−158 In this context, Donohoe found that the use of hypervalent iodine reagents in fluorinated solvents could induce SET-triggered [2 + 2] cycloadditions of anethole and its derivatives.159 However, the aromatic ring must remain electron-rich. Again, oxidative SET-triggered cyclobutane formations are only feasible when a redox tag is present. Mechanistic studies with Compton using an electrochemical technique revealed that a notable structural motif in successful [2 + 2] dimerizations is the presence of an aromatic methoxy group (Scheme 49).160 In the absence of an aromatic methoxy group, the initial oxidative SET would be difficult due to high redox potentials. We can hypothesize that the desired cycloadduct was hardly obtained even if the initial SET was possible, since an efficient intramolecular SET from the aromatic ring to the cyclobutyl radical might not be expected. This hypothesis will be addressed later. Recently, photocatalysts also have found significant applications in synthetic organic chemistry, enabled by “energy transfer” mechanisms. Since these reaction mechanisms are currently elusive from the viewpoint of a formalism, we will not discuss them further.161−167 However, we strongly believe such an energy transfer mechanism will be the key to creating novel reactivity space in the field of synthetic organic chemistry,

5. (PHOTO)CHEMICAL SET-TRIGGERED DIELS-ALDER REACTIONS 5.1. Historical Background

So far, we have mainly focused on SET-triggered [2 + 2] cycloadditions because of their historic background and mechanistic importance. However, SET-triggered Diels−Alder reactions, which are [4 + 2] cycloadditions between a diene and a dienophile, also have immense importance in synthetic organic chemistry.168−179 Since cyclohexenes formed through Diels−Alder reactions are six-membered, they have little ring strain. In contrast, [2 + 2] cycloadditions form four-membered cyclobutanes, which have greater ring strain. Therefore, Diels− Alder reactions are more energetically favorable than [2 + 2] cycloadditions and cyclohexenes are more easily constructed than cyclobutanes. Even so, strict electronic matching is definitely required for successful Diels−Alder reactions, namely, one reaction partner should be electron-rich and the other electron-deficient. Therefore, Diels−Alder reactions between both electron-rich dienes and dienophiles must be creatively designed. In this context, SET-triggered approaches have proven to be highly effective to promote such electronically mismatched S


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Scheme 51. SET-Triggered Diels-Alder Reaction of transAnethole (1)

Diels−Alder reactions. Oxidative SET can generate electrondeficient radical cations of either the diene or dienophile, which can then be trapped by other electron-rich reaction partners. Arguably, SET processes are the most straightforward approaches to realize polarity inversion, more commonly called “umpolung,” which is a classical but central concept in which reversal of the normal reactivity of the molecules being studied occurs. The prototypical example of a SET-triggered Diels− Alder reaction is the [4 + 2] dimerization of CHD (13) (Scheme 15). The transformation was first studied under photochemical conditions by Freeman180 and Hammond181 and was carefully and systematically studied by Bauld.84,85 Bauld found that the desired product was only obtained in low yield under thermal conditions; however, the reaction proceeded smoothly under umpolung conditions (Scheme 50).83 Chemical oxidative SET using a bench stable aminium

the initial chemical oxidative SET took place from transanethole (1) to generate the corresponding radical cation (1·+). On the basis of the ensuing bond formations, the styrenic double bond must possess significant radical and/or cation character, since otherwise impossible-to-construct carbon− carbon bonds at these positions were formed. The generated radical cation (1·+) was then trapped by neutral dienes to afford Diels−Alder cycloadducts. This reaction was elegantly revived by Yoon in 2011.183 Yoon revisited the oxidative SET-triggered Diels−Alder reactions of trans-anethole (1) in the realm of photoredox catalysis. When isoprene was used as a model diene, the reaction did not proceed at all under thermal conditions, whereas the desired Diels−Alder cycloadduct was obtained in excellent yield under photochemical SET conditions (Scheme 52). They significantly expanded the scope of the reactions and

Scheme 50. [4 + 2] Dimerization of 1,3-Cyclohexadiene (13)

Scheme 52. SET-Triggered Diels-Alder Reactions of transAnethole (1) and the Styrene (3)

salt gave a conjugated cyclohexadienyl radical cation, which was then trapped by neutral CHD (13). The formed cyclohexenyl radical cation was no longer conjugated; therefore, it was expected to oxidize the starting CHD (13) to complete the overall net-redox neutral Diels−Alder reaction and trigger the radical cation chain process. As represented by the [4 + 2] dimerization of CHD (13), many examples have been reported to demonstrate that SET-triggered Diels−Alder reactions are possible even in the absence of electron-rich aromatic rings (i.e., without a redox tag). This might be explained by the above-mentioned ring strains, namely, the barrier to be overcome for the formation of a six-membered cyclohexene is lower than that of a four-membered cyclobutane. Although several SET-triggered Diels−Alder reactions have been achieved so far, it should also be noted that the early examples of such reactions were mainly performed between two dienes. In these cases, reaction mechanisms are rather elusive since redox potentials of both dienes are expected to be similar, so it is difficult to determine where the initial SET occurs.

their synthetic utility with the accompanying unique mechanistic study.184 Substrates lacking an aromatic methoxy group (3) were unsuccessful dienophiles. Again, the oxidation potential of the substrate without an aromatic methoxy group (3) is significantly higher than that of trans-anethole (1); therefore, it is rather difficult to induce oxidative photochemical SET from these substrates. However, we also can expect that the desired Diels−Alder cycloadduct is not obtained even if the initial SET is possible, since an effective intramolecular electron donor (i.e., redox tag) is absent (Scheme 53). Although intermediate with a long bond analogous to that of cyclobutane formation was not mentioned here for the SET-triggered Diels−Alder reaction, intramolecular SET processes might be crucial to complete the cyclohexene formation. Instead of ruthenium and iridium, Ferreira and Shores demonstrated the potential of a chromium photocatalyst by

5.2. SET-Triggered Diels−Alder Reactions of trans-Anethole

Clarification of the mechanisms of SET-triggered Diels−Alder reactions was addressed by the use of styrenes and electron-rich olefins as dienophiles in the reactions. In this context, we now refocus on trans-anethole (1) as a dienophile in the realm of SET-triggered Diels−Alder reactions, which was first reported by Bauld in 1986 (Scheme 51).182 In the original paper, although the yields were moderate, the SET-triggered Diels− Alder reactions of trans-anethole (1) were reported in combination with several simple dienes, such as isoprene (68). Importantly, the redox potential of trans-anethole (1) was significantly lower than those of the simple dienes. Therefore, T


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Scheme 53. Expected Reaction Mechanism of the SETTriggered Diels-Alder Reaction

Scheme 55. Effect of Additional Oxygen Atom

using the SET-triggered Diels−Alder reactions of transanethole (1) and its derivatives.185 Interestingly, they first optimized the reaction conditions by using the prototypical example of the reaction, namely, [4 + 2] dimerization of CHD (13), since the chromium photocatalyst has a stronger redox potential than the ruthenium or iridium variants. The chromium photocatalyst effectively induced the photochemical oxidative SET-triggered [4 + 2] dimerization of CHD (13), while the ruthenium variant was less effective (Scheme 54).

Scheme 56. Disadvantageous Effect from an Additional Aromatic Methoxy Group

Scheme 54. SET-Triggered [4 + 2] Dimerization of 1,3Cyclohexadiene (13)

These results clearly suggested that the redox potential of the photocatalyst was important to induce photochemical SET processes from the substrate being studied. Under optimized conditions, they then turned their attention to the reactions of trans-anethole (1) and its derivatives. In addition to Yoon’s report, they also showed a wide range of scope and a great synthetic utility of the reactions with the subsequent unique mechanistic study with Rappé.186 However, even a chromium photocatalyst with a stronger redox potential was not sufficient to induce the SET-triggered Diels−Alder reaction of a substrate without an aromatic methoxy group (3). Any additional oxygen atoms, with the exception of the aromatic methoxy group, should be protected with an electron-withdrawing group, presumably to decrease the nucleophilicity (Scheme 55). They assumed that a competitive intramolecular donation of the oxygen to the radical cation, possibly at the olefinic double bond, would take place to prevent trapping by the dienes, which are consistent with earlier reports.187−191 Importantly, Yoon (Scheme 56),183 Ferreira, and Shores (Scheme 57)185 observed disadvantageous effects from an additional aromatic methoxy group. When a second methoxy group was added to trans-anethole (1), a decrease in the yields was observed depending on the substitution pattern. Yoon also used a substrate with three aromatic methoxy groups (71) and obtained the desired Diels−Alder cycloadduct (72) in good yield; however, a longer reaction time was needed. At first glance, the additional aromatic methoxy groups should be


advantageous since these electron-donating groups can effectively activate the styrenic double bond to the oxidative SET process (i.e., the methoxy groups are expected to increase the electron density of the aromatic ring and thus decrease their oxidation potentials). This should have a positive impact on the U


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equilibrium between the aromatic radical cation and olefinic radical cation regulated by intramolecular SET is highly biased to the aromatic form, which cannot participate in further bond formations. We predict that if the equilibrium is biased to the olefinic form, and if it were trapped by the diene, the intramolecular SET must be highly effective from the aromatic ring with additional methoxy groups. Currently, we are not able to realize such a biased equilibrium. Even so, we believe that the idea would be helpful to take further advantage of radical cation reactivity.

reaction since the substrates become easier to oxidize by photocatalysts. These observations can be reasonably and simply understood by a formalism. On the basis of the following chemical transformations, the radical and/or cation reactivity should localize on the styrenic double bond, otherwise it would be impossible to form carbon−carbon bonds at these positions. Because an electron-donating methoxy group can stabilize the radical and/or cation on the aromatic ring, little reactivity exists on the styrenic double bond when two or more aromatic methoxy groups are installed. In other words, the radical and/or cation would mainly localize on the aromatic ring, thus rendering it unable to participate in further bond formations. We also can illustrate the equilibrium between the aromatic radical cation and olefinic radical cation, which are converted via intramolecular SET processes (Scheme 58). The radical cation stabilized with additional methoxy

5.3. Where Is the Radical and/or Cation?

Unique and distinctive reactivity can even be discerned from the way the reactions are written. Let us examine the case of the radical cation of trans-anethole (1) (Figure 6), which has been repeatedly covered in this Review. Yoon expressed it in a classical distonic form, where radical and cation are localized on the α- and β-positions of styrene, respectively.183 Nicewicz depicted it as a totally delocalized form, which is perhaps the fairest way to describe the radical cation of trans-anethole (1) from the viewpoint of quantum chemistry.150 On the other hand, Donohoe expressed it in a classical form but differently from Yoon, where the radical and cation are entirely separated on the β-position of styrene and oxygen atom of the aromatic methoxy group, respectively.159 In sharp contrast, the totally delocalized form was seen in the mechanistic paper by Compton, which seems to be suited to analytical chemistry.160 Ferreira and Shores employed that the partially delocalized form, namely, the radical cation is distributed over two olefinic carbons.185 Nowadays, the computational approach can easily depict the “real” form of the radical cation especially for such a small molecule, and thus discussions in the way of writing the reaction may not have significant scientific meaning. Even so, this diversity represents the unique and distinctive reactivity of the radical cation, which is reflected in the way chemists think.

Scheme 58. Expected Reaction Mechanism of the DielsAlder Reactions

5.4. Anodic SET-Triggered Diels−Alder Reactions

We also addressed the Diels−Alder reactions of trans-anethole (1) by using the anodic oxidative SET process.192 We envisioned that a similar mechanistic picture based on the intramolecular SET approach would be illustrated by the reaction. By using an electrochemical approach, oxidation potentials of the molecule being studied should not be an issue since redox potentials are switchable in a facile and precise manner. Therefore, we expected it would be possible to address the open question postulated several times, namely, why substrates without aromatic methoxy groups were unsuccessful in most reactions. We confirmed that the anodic oxidative SET was indeed effective for the Diels−Alder reaction between trans-anethole (1) and isoprene (68) as models, affording the desired cycloadduct in excellent yield (Scheme 59). Through careful monitoring, we also found that the reaction was

groups is expected to be relatively long-lived and thus have opportunities for nonproductive reduction and/or back electron transfer. This explanation is in good accordance with the fact that the reaction of the substrate with three methoxy groups required a significantly longer time to be completed. Therefore, even the initial SET would be favored in the presence of additional aromatic methoxy groups, the

Figure 6. Several expressions of the radical cation of trans-anethole (1).150,159,160,183,185 V


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cycloadditions, the enol ether radical cation (8·+) could still be trapped by olefins even in the absence of the aromatic methoxy group, leading to an olefin metathesis product (Scheme 60). Unfortunately, we were not able to obtain the desired Diels− Alder cycloadduct (70) at all from the styrene without the aromatic methoxy group (3). With these observations, we concluded that the reaction proceeded via stepwise SET processes as follows (Scheme 61).

completed using 0.1 F/mol of electricity, unambiguously suggesting the involvement of a radical chain process. Scheme 59. Anodic SET-Triggered Diels-Alder Reactions

Scheme 61. Plausible Reaction Mechanism of the Anodic SET-Triggered Diels-Alder Reaction

On the basis of cyclic voltammetric studies, the oxidation potentials of trans-anethole (1) and the substrate without an aromatic methoxy group (3) were measured to be 1.07 and 1.51 V versus Ag/AgCl, while that of isoprene (68) was 1.83 V versus Ag/AgCl (Figure 7). Therefore, selective SET would be

Figure 7. Oxidation Potential (vs Ag/AgCl) of the Substrates (1, 3, 68).

possible even for the substrate without a methoxy group (3) in the presence of isoprene (68). Indeed, when the reaction was carried out with enough redox potential for the substrate without a methoxy group (3), an electric current was observed, clearly indicating that anodic oxidative SET did take place. On the basis of the oxidation potentials, the initial SET took place from the styrene (3) to generate the corresponding radical cation (3·+). There are two possibilities for the generated radical cation (3·+), decomposition or trapping by isoprene (68). Further creative experiments are needed to entirely rule out the first possibility. Even so, if the reaction took place in analogy with the anodic oxidative SET-triggered [2 + 2]

The initial SET took place from trans-anethole (1) to generate the radical cation (1·+), which we prefer to express in classical form similar to Yoon,183 but with the radical and cation localized in opposite fashion. The radical cation (1·+) was then trapped by isoprene (68) to form the cyclohexenyl framework. The intermediate was regarded as a cyclohexenyl radical cation (69c·+), which must be reduced immediately by an intramolecular electron donor, namely, a redox tag. Intramolecular SET from the electron-rich aromatic ring to the cyclohexenyl moiety completed the formation of neutral cyclohexene and

Scheme 60. Plausible Reaction Mechanisms in the Absence of the Redox Tag

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thus formed a relatively long-lived aromatic radical cation (69a·+), which then induced the oxidative SET from the starting trans-anethole (1), triggering the radical cation chain process. The intramolecular SET process regulated by a redox tag seems to be crucial for the reaction and thus, it might be that the styrene without an aromatic methoxy group was unsuccessful since the intramolecular SET process was not effective. In addition, we also observed similar disadvantageous effects of additional aromatic methoxy groups, as Yoon,183 Ferreira, and Shores185 observed earlier (Scheme 62). Clearly, the

Scheme 63. Plausible Dual Equilibria Converted via Intramolecular SET Processes


participate in [4 + 2] dimerization.185 Since the oxidation potential of CHD (13) is significantly higher than that of transanethole (1), the initial photochemical oxidative SET was expected to occur from trans-anethole (1) to generate the radical cation (1·+), which could then be trapped by CHD (13) to give the desired Diels−Alder cycloadduct (73) selectively. However, they obtained not only the expected Diels−Alder cycloadduct (73) but also the dimer of CHD (14), with a significant amount of unreacted trans-anethole (1) (Scheme 64). They explained this product distribution by known kinetic Scheme 64. Photochemical SET-Triggered Diels-Alder Reaction between trans-Anethole (1) and 1,3Cyclohexadiene (13)

electron density, which is equivalent to the oxidation potential, of the aromatic ring must be balanced. The styrenic double bond should be activated for the initial oxidative SET, but the radical cation must not be stabilized too much, otherwise no radical and/or cation reactivity would exist on the styrenic double bond. The reaction could also be understood by dual equilibria converted via intramolecular SET processes, namely, between aromatic radical cation and styrenic radical cation, and cyclohexenyl radical cation and aromatic radical cation (Scheme 63). Obviously, both intramolecular SET processes were regulated by the aromatic redox tag.

data, namely, the rate of CHD (13) reacting with the radical cation of itself (13·+) is faster than the rate of it reacting with the radical cation of trans-anethole (1). Additionally, this observation meant that the initial photochemical oxidative SET was also possible from CHD (13) even in the presence of transanethole (1). In order to definitively elucidate the reaction mechanism, we designed an anodic oxidative SET-triggered Diels−Alder reaction using a silica gel-supported substrate.193 It is wellknown that electron transfer between two solid phases hardly takes place. Therefore, in organic electrochemistry, solid phasesupported substrates are usually not oxidized or reduced at the electrodes. On the basis of this fact, solid phase-supported substrates have been creatively used in synthetic organic electrochemistry.194−199 We first searched for dienes that could be easily oxidized even in the presence of trans-anethole (1) and found that 9-methylanthracene (74) has a lower oxidation potential than that of trans-anethole (1). When the anodic oxidative SET-Triggered Diels−Alder reaction was carried out between trans-anethole (1) and 9-methylanthracene (74), the desired Diels−Alder cycloadduct (75) was obtained in excellent

5.5. Bidirectional Access to SET-Triggered Diels−Alder Reactions

Most early examples of SET-triggered Diels−Alder reactions were carried out between two dienes, and thus it can be difficult to tell where the initial oxidative SET occurred. By using transanethole (1) as a dienophile, with an oxidation potential significantly lower than that of a diene such as isoprene (68), the initial oxidative SET takes place from trans-anethole (1) to generate the radical cation (1·+), triggering further chemical transformations. In this context, however, Ferreira and Shores reported an interesting observation. They carried out the photochemical oxidative SET-triggered Diels−Alder reactions of trans-anethole (1) with CHD (13), which potentially can X


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form instead of a radical cation. Here, we simply refer to these processes as anodic oxidation. In such anodic oxidations, electrons are reagents rather than catalysts and radical cation chain processes are not involved. In 1989, pioneering work capitalizing on intramolecular SET was reported in the field of synthetic organic electrochemistry by Moeller. Prior to their findings, anodic oxidative methoxylation of an amide (80) in the presence of a nonsubstituted phenyl ring had already been reported by Shono (Scheme 67).200 In this case, the N-α position was selectively methoxylated (81), meaning that the anodic oxidation took place at this position, generating an iminium cation (82+) (Scheme 68). Moeller prepared a series of amides with methoxyphenyl rings (83−85) and tested for anodic oxidative methoxylation (Scheme 69).201 On the basis of the oxidation potentials, the anodic oxidation occurred selectively at the electron-rich aromatic ring, which led to methoxylation at the benzylic position instead of the N-α position. As expected, anodic oxidative methoxylation of the amide in the presence of the 4-methoxyphenyl ring (83) gave the benzylic methoxylated product (86) selectively, while N-α methoxylation (87) was not observed. However, in the cases of the anodic oxidative methoxylation of the amides with 3- (84) and 2-methoxyphenyl rings (85), N-α methoxylated products (89, 91) were selectively isolated instead of the corresponding benzylic methoxylated products (88, 90). The position where methoxylation took place could be used as a probe to detect where anodic oxidation occurred, equivalent to where the cation formed. Moeller proposed an equilibrium in the radical cation state, after the initial anodic oxidative SET process, between the aromatic radical cation (84a·+) and amide radical cation (84am·+), which were rapidly converted by the intramolecular SET process (Scheme 70). On the basis of the proposed mechanism, the N-α position was selectively methoxylated even if the initial anodic oxidative SET occurred from the aromatic ring, since the radical and/or cation would be transferred via an intramolecular SET process. They further studied this unique mechanistic proposal to find that the selectivity of the reactions was dependent on the substitution pattern of the phenyl ring.202

yield (Scheme 65). Simply based on the oxidation potentials, the initial anodic oxidative SET took place from 9Scheme 65. Anodic SET-Triggered Diels-Alder Reaction between trans-Anethole (1) and 9-Methylanthracene (74)

methylanthracene (74) to generate the radical cation (74·+), which was then trapped by trans-anethole (1), namely, the reaction proceeded in opposite fashion. However, the other possibility that the initial SET occurred from trans-anethole (1) and drove the reaction could not be entirely ruled out. Therefore, we prepared both silica gel-supported anethole (76) and anthracene (77) and used them as substrates to verify these pathways (Figure 8). By using cyclic voltammetry, we clearly confirmed that the electron transfer between the silica gel-supported substrates and electrode was severely limited. These results suggested that there was almost no possibility for the silica gel-supported substrates to be involved in anodic oxidative SET processes under the reaction conditions. Gratifyingly, we confirmed that the radical cation of 9-methylanthracene generated by the initial anodic oxidative SET was long-lived enough to reach the silica gel-supported anethole (76) and drive the reaction, affording the desired Diels−Alder cycloadduct (78) (Scheme 66). Thus, an anodic oxidative SET-triggered Diels−Alder reaction was possible between silica gel-supported anethole (76) and free 9methylanthracene (74), clearly suggesting that the reaction could be triggered by the anodic oxidative SET from 9methylanthracene (74). We also confirmed that the opposite combination, the reaction between free trans-anethole (1) and silica gel-supported anthracene (77), also gave the desired Diels−Alder cycloadduct (79). These results clearly indicated that anodic oxidative SET-triggered Diels−Alder reactions potentially proceeded via the generation of radical cations of either the dienophile or diene.

6.2. Anodic SET-Oxidative Competition Reactions

Moeller then questioned how general such intramolecular SET processes were, more specifically, whether they were dependent on the presence of an aromatic ring. While we have introduced several intramolecular SET processes in this Review, aromatic rings existed in all cases. In order to generalize the importance of such intramolecular SET processes, Moeller designed an enol ether with a dithioketal (92), which was a well-known readily oxidized moiety.203 The initial anodic oxidative SET is rationally expected to take place at the dithioketal moiety, more specifically, on the sulfur atom to give the corresponding radical cation (92s·+) (Scheme 71). On the basis of cyclic voltammetric studies, the oxidation potential of the enol ether is significantly

6. ANODIC SET OXIDATIONS 6.1. Anodic SET-Oxidative Methoxylations

Intramolecular SET processes are more elusive than the intermolecular versions, especially in synthetic organic chemistry. Therefore, the number of studies capitalizing on intramolecular SET events is limited. So far, we have focused on net-redox neutral reactions to discuss the importance of intramolecular SET processes. In this chapter, we extend the discussion to intramolecular SET processes by oxidation. In these cases, anodic oxidative SET generally occurs twice with deprotonation; therefore, a simple cation intermediate would

Figure 8. Structure of Silica Gel-Supported Substrates. Y


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Scheme 66. Anodic SET-Triggered Diels-Alder Reactions of Silica Gel-Supported Substrates

of the dithioketal (92s·+) would lead to intermolecular methoxylation, while the enol ether radical cation (92e·+) would be trapped by an intramolecular alcohol. Therefore, even if the equilibrium between the radical cation of the dithioketal (92s·+) and enol ether radical cation (92e·+) was highly biased to the former radical cation, rapid intramolecular trapping of the latter radical cation could compete with intermolecular methoxylation. If this scenario was in play, the enol ether radical cation would be removed from the equilibrium and thus the rapid intramolecular SET process would provide additional enol ether radical cation, which would then be trapped intramolecularly by the alcohol to give the desired cyclized product (94). The desired cyclized product was obtained in good yield selectively instead of the undesired methoxylation (93) (Scheme 72). Moeller further demonstrated that the scenario worked nicely by using a different enol ether substrate with a dithioketal, clearly highlighting the importance of the intramolecular SET processes.204 In addition to an alcohol, Moeller reported that intramolecular trapping of the olefinic radical cation was also possible with p-toluene sulfonamide, which benefited greatly from the use of basic reaction conditions (Scheme 73).205,206 When the sulfonamide was used instead of an alcohol, a complicated yet highly interesting reaction mechanism involving the intramolecular SET process could be proposed (Scheme 74). The addition of a suitable base was expected to deprotonate the sulfonamide (95), generating two possible intermediates in combination with the anodic oxidative SET

Scheme 67. Anodic SET-Oxidative Methoxylation of the Amide (80)

Scheme 68. Plausible Reaction Mechanism of the Methoxylation of the Amide (80)

higher than that of the dithioketal, so this expectation should be reasonable. However, if the radical cation of the dithioketal (92s·+) and the enol ether radical cation (92e·+) were in equilibrium, and interconverted by a rapid intramolecular SET process, the synthetic outcome would be different. In this case, the substrate was creatively designed, namely, the radical cation

Scheme 69. Anodic SET-Oxidative Methoxylation of the Amides (83−85)

Z


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Scheme 70. Proposed Reaction Mechanism of the Methoxylation of the Amide (84)

Scheme 71. Expected Reaction Mechanism of an Anodic SET-Oxidative Coupling of the Substrate (92)

Scheme 74. Expected Reaction Mechanism of the Anodic SET-Oxidative Coupling of the Substrate (95)

intermediates should be in equilibrium via a rapid intramolecular SET process, and either can potentially participate in subsequent reactions. Namely, via the zwitterionic radical, a nucleophilic addition of sulfonamide anion to the olefinic radical cation can formally be proposed, while the radical addition of the nitrogen radical to the neutral olefin would be reasonable via the neutral radical. Since the same synthetic outcomes (97) would be achieved from either intermediate, it can be complicated to distinguish these two mechanisms. The cyclopropane system has been widely employed to study the kinetics of radical-driven reactions as a representative radical clock compound. However, it seems to be only applicable to reactions where neutral radicals are involved and thus the study of kinetics for radical ion-driven reactions is still challenging.207−209 In order to address such a seemingly elusive mechanistic discussion, Moeller devised a competition experiment using electron-rich olefins possessing two potential trapping groups.210−212 Moeller demonstrated that this approach was especially useful to investigate the mechanism of the above-mentioned trapping of olefinic radical cations by sulfonamide. Here, both an alcohol and a p-toluene sulfonamide were tethered to a readily oxidizable electronrich olefin, and the synthetic outcomes obtained under the conditions of anodic oxidation were used to probe the reaction mechanism (Scheme 75). They assumed that the zwitterionic radical (99z·) pathway, a nucleophilic addition of sulfonamide

Scheme 72. Anodic SET-Oxidative Coupling of the Substrate (92)

Scheme 73. Anodic SET-Oxidative Coupling of the Substrate (95)

process, namely, a zwitterionic radical (96z·) and a neutral radical (96·). After deprotonation of the sulfonamide to afford the corresponding anion (96‑), anodic oxidative SET from the electron-rich olefin would generate the zwitterionic radical (96z·), while the neutral radical (96·) would be generated if anodic oxidative SET took place from the nitrogen atom. These AA


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Scheme 75. Proposed Reaction Mechanism of the Competition Experiment

Yoshida called the functional group containing such readily oxidizable elements an electroauxiliary. In general, the initial anodic oxidative SET was designed to take place selectively at the readily oxidizable atom to generate the radical cation species, which led to the generation of a cation at an adjacent position via carbon-heteroatom cleavage. In other words, the electroauxiliary was cleaved off from the molecule being studied after the initial anodic oxidative SET to generate the corresponding cation or radical. In this case, intramolecular SET might formally be involved; however, the distance that the electron is transferred is relatively short. The more important aspect of this work is that anodic oxidation is possible under relatively lower oxidation potentials and thus, otherwise impossible chemical transformations can be realized. Since their work has been comprehensively reviewed, we have omitted an item-by-item discussion, but we provide one typical example, the N-α functionalization of pyrrolidine. In analogy with the anodic oxidative methoxylation reported by Shono and Moeller, the anodic oxidation of pyrrolidine (100) gave the N-α methoxylated product (101) (Scheme 76).

anion to the olefinic radical cation, should involve a significant change in polarity and thus would be sensitive to the solvent used. This would not be the case for the neutral olefin (99·) pathway, a radical addition of nitrogen radical to the neutral olefin, since there would be no change in polarity. Together with theoretical and electroanalytical studies, they concluded that the anodic oxidative reaction between an electron-rich olefin and toluene sulfonamide under basic conditions exhibited a radical-like mechanism, the neutral olefin pathway. They proposed that the initial anodic oxidative SET occurred at the sulfonamide anion to generate a neutral nitrogen radical (99·), which then participated in the radical addition to the electronrich olefin. Importantly, rapid intramolecular SET from the electron-rich olefin to the nitrogen radical was also possible, which converted the neutral radical (99·) to the zwitterionic radical (99z·), and the generated olefinic radical cation would be trapped by the alcohol rather than the sulfonamide anion. Thus, the intramolecular SET process has the potential to control synthetic outcomes. The reactivity of the nitrogen radical generated by the anodic oxidative SET process was recently further generalized by Xu using both direct and indirect approaches in the presence of suitable redox mediators.213−218 Xu significantly expanded the synthetic utility of nitrogen radicals, including amidyl and amidinyl, which should find further applications in the field of synthetic organic chemistry. Since these transformations are now regarded as neutral radical-driven reactions rather than radical ion-driven, we have omitted their item-by-item discussion.

Scheme 76. Anodic SET-Oxidative N-α Functionalization of Pyrrolidine (102)

6.3. Lowering Oxidation Potentials

Moeller clearly demonstrated that bond formations and/or cleavages did not always take place where the radical and/or cation initially formed. For example, even if the initial anodic oxidative SET was rationally expected to occur at the dithioketal moiety, rapid and effective intramolecular SET processes can generate distinctive reactivity at the remote enol ether moiety. In other words, this intramolecular SET could lower the oxidation potential of the enol ether. More specifically, anodic oxidation even at a potential where an enol ether usually cannot be involved could also generate an enol ether radical cation via initial formation of the radical cation of the dithioketal. This concept should expand the synthetic utility of anodic oxidative SET-triggered reactions, since higher oxidation potentials generally cause undesired side reactions. This concept had already been proposed and established by Yoshida.219 While Moeller used a dithioketal as a readily oxidizable moiety, Yoshida focused on the use of readily oxidizable elements, including silicon, tin, and sulfur.

However, this transformation requires a relatively high oxidation potential and thus, for example, highly electron-rich aromatic rings are generally incompatible. The N-α allylation using allyltrimethylsilane (102) was used as a model reaction, since the oxidation potential of allyltrimethylsilane (102) was significantly lower than that of pyrrolidine. Therefore, anodic oxidative SET took place selectively from the allyltrimethylsilane (102) and no desired allylated product (103) was obtained via the direct reaction. In this context, for example, the introduction of trimethylsilyl (104), phenylsulphanyl (105), or trimethoxyphenyl (TMP) groups (106) to the N-α position significantly lowered the oxidation potential of pyrrolidine, and thus, the selective anodic oxidative SET was made possible even AB


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in the presence of allyltrimethylsilane (102) to give the desired allylated product (103) (Scheme 77).

Scheme 79. Expected Reaction Mechanism of the SETTriggered Reactions Assisted by Redox Auxiliary

Scheme 77. Anodic SET-Oxidative N-α Functionalization of Pyrrolidine (102)

7. OTHERS

More recently, Yoon modernized the concept of the electroauxiliary, calling it a “redox auxiliary,” and focused on the use of radical cation reactivity.220 The working mechanism of the redox auxiliary is more similar to Moeller’s dithioketal method than the electroauxiliary. Yoon prepared aryl vinyl sulfides (107) as substrates for photochemical oxidative SETtriggered Diels−Alder reactions and [2 + 2] cycloadditions (Scheme 78). These reactions can be understood in analogy

7.1. Reductive SET-Triggered Reactions

So far, we have been dealing only with oxidative SET-triggered reactions, involving radical cations, with special emphasis on net redox-neutral transformations. For the following two reasons, we only provide limited examples of the opposite version, reductive SET-triggered net redox-neutral reactions. First, reductive SET-triggered net redox-neutral reactions involving radical anion chain mechanisms are rather rare. They were first reported by Simonet in 1990 (Scheme 80),221

Scheme 78. SET-Triggered Reactions Assisted by Redox Auxiliary

Scheme 80. Reductive SET-Triggered [2 + 2] Dimerization

two decades after the first report on the oxidative version. Second, most photoredox catalysis has focused on the use of photochemical reductive SET processes rather than oxidative versions, and they have recently been reviewed comprehensively. In this Review, we point out that intramolecular SET processes would also be the key for reductive SET-triggered net redox-neutral reactions. Reductive SET-triggered net redox-neutral reactions can be understood in analogy with the oxidative SET-triggered [2 + 2] dimerization of NVC (Scheme 81). Simonet reported that the corresponding [2 + 2] dimerization of aryl vinyl sulfones (108) was triggered by a cathodic reductive SET process. Simonet proposed that the reaction involves a radical anion chain mechanism, namely, initial cathodic reductive SET was expected to take place on the electron-deficient vinyl moiety, generating the corresponding olefinic radical anion (108·‑), which was then trapped by the neutral aryl vinyl sulfone (108) to construct a cyclobutyl framework (109·‑). Since this intermediate was still in radical anion form, it was then oxidized by the starting aryl vinyl sulfone to trigger the radical anion chain process. We can expect that intramolecular SET

with the reactions of trans-anethole (1). Like the dithioketal moiety, sulfide is also known to be readily oxidized to a radical cation (Scheme 79). Its distinctive reactivity is transferred to the olefinic double bond formally via an intramolecular SET process, which is then trapped by a diene or dienophile to construct a cyclohexene or cyclobutane framework, respectively. Although further experiments are definitely needed to reveal the overall picture of the reactions, we expect that the respective ring formation is completed through reduction by the sulfide. Namely, rapid and effective intramolecular SET from sulfide to the cyclohexenyl or cyclobutyl radical cation would be crucial for the overall transformations. On the basis of such expectations, we believe that sulfide has also proven to be a powerful yet simple motif to regulate intramolecular SET processes in addition to electron-rich aromatic rings. AC


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SET process. Although it is reasonable to conclude that such intramolecular SET processes would be important for the cyclobutane formation, it is not crucial since the desired cyclobutane (111) was obtained even from methoxyphenyl vinyl sulfone (110). In 2001, Krische reported intramolecular [2 + 2] dimerization of a bis-aryl enone (112) catalyzed by metals, including cobalt and copper, and the intermediacy of a radical anion species in the reactions was suspected (Scheme 83).222,223 Further mechanistic studies with Bauld clearly

Scheme 81. Plausible Reaction Mechanism of Reductive SET-Triggered [2 + 2] Dimerization

Scheme 83. Chemical SET-Triggered [2 + 2] Dimerization of the Bis-Enones

demonstrated that the reactions could be regarded as net redox-neutral reductive SET-triggered radical anion chain processes (Scheme 84).224−226 The initial reductive SET was

processes occur in exactly the opposite fashion to what we have seen in this Review so far. Namely, intramolecular SET from an electron-rich cyclobutyl radical anion to an electron-deficient aromatic ring would be the key to the completion of cyclobutane formation, and indeed disadvantageous effects were observed when an electron-rich aryl vinyl sulfone was used instead of electron-deficient variants (Scheme 82). Since they

Scheme 84. Plausible Reaction Mechanism of SET-Triggered [2 + 2] Dimerization of Bis-Enone (112)

Scheme 82. Unfavorable Reductive SET-Triggered [2 + 2] Dimerization

expected to occur on either enone moiety, generating the corresponding radical anion (112·‑), which was then trapped by the other enone to construct the cyclobutane framework (113). Since the electron-rich aryl enone (114), possessing a methoxyphenyl ring, was unsuccessful in the reaction, even using the electrochemical approach, we can speculate on the importance of the intramolecular SET process to complete the cyclobutane formation. Namely, the trapping of the initially generated enone radical anion (112·‑) by a neutral one gave a

employed an electrochemical approach, suitable redox potentials were applied to induce initial cathodic reductive SET even from electron-rich aryl vinyl sulfones, which were not expected to be readily reduced. Therefore, the disadvantageous effects caused by the electron-rich aromatic ring would be due to its poor ability to accept an electron via the intramolecular AD


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Scheme 85. Photochemical Reductive SET-Triggered [2 + 2] Dimerization of the Bis-Enones

transient cyclobutyl radical anion (113c·‑), which must be immediately oxidized by an intramolecular electron acceptor. The aromatic ring here can be considered a redox tag, which functioned in the opposite redox fashion as compared to the cases discussed so far. In 2008, as one of the first examples in this field, Yoon revisited the reductive SET-triggered [2 + 2] cycloadditions in the realm of photoredox catalysis.48 The reaction mechanisms can be similarly understood as radical anion chain processes; however, it should be noted that the cyclobutane (115) was successfully obtained even from electron-rich aryl enones, which was unsuccessful in the early examples (Scheme 85). Importantly, they found that the presence of lithium cation was essential for the reactions. The lithium cation increased the solubility of the ruthenium photocatalysts and activated the enone to the reductive SET process as a Lewis acid. Later, Yoon also reported that lithium cation also stabilized the radical anion intermediates, which presumably extended the lifetime of the transient cyclobutyl radical anion long enough to be oxidized by the ineffective intramolecular SET process and/or the intermolecular version even in the absence of an electrondeficient aromatic ring.39 Yoon also noted that the choice of Lewis acid dramatically changed the reaction mode, realizing effective control of synthetic outcomes of photochemical reductive SET-triggered reactions involving radical anion chain processes. The [2 + 2] cycloadditions were also successfully applied to the intermolecular versions, thus expanding the synthetic utility significantly (Scheme 86).227

Scheme 87. Unsuccessful Photochemical Reductive SETTriggered [2 + 2] Cycloadditions


Scheme 86. Intermolecular Photochemical Reductive SETTriggered [2 + 2] Cycloadditions namely, the radical and/or anion reactivity initially formed at the enone was transferred to the cyclobutyl moiety to induce carbon−carbon bond cleavage. Again, this is just the opposite redox pathway regulated by intramolecular SET processes, which we have been discussing so far. 7.2. Oldest and Latest; Carbazole

Although further experiments are needed, we can emphasize the importance of intramolecular SET processes in such reductive SET-triggered [2 + 2] cycloadditions in two ways. First, even in the presence of a radical anion stabilizing lithium cation, at least one aromatic ring, whether electron-rich or deficient, is required for successful transformations (Scheme 87). Although it is reasonably understood that aliphatic enones are less readily reduced than their aromatic variants, we also may suspect that aromatic rings are crucial to oxidize the transient cyclobutyl radical anion via intramolecular SET processes. Second, the isomerization of the obtained cyclobutane from the cis to trans form is indeed observed under photochemical SET conditions (Scheme 88). In this case, initial reductive SET is expected to take place on the enone moiety; however, the ring-opening reaction occurred at the cyclobutyl moiety, causing its isomerization. This observation clearly indicated the importance of intramolecular SET processes,

As mentioned in the introduction, various catalysis are utilized in modern synthetic organic chemistry, including transition metals and their complexes, organocatalysts, Lewis acids and bases, protons, and electrons. Synthetic organic chemists must address how these traditional catalysis methods are effectively merged with redox catalysis to realize chemical transformations that are otherwise impossible or difficult to achieve. This is also called a dual, or even triple, catalysis strategy. Although some catalysts are indeed incompatible with each other, SET catalysis, especially photochemical SET, has found remarkable applications. Since this strategy has recently been reviewed comprehensively,53,228−230 we have omitted an item-by-item discussion. Finally, we introduce one of the latest examples utilizing the oldest redox active moiety known, carbazole, to enable the carbon−carbon bond formation that generates a quaternary stereogenic center, which is recognized as one of the AE


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most challenging transformatons in modern synthetic organic chemistry. Enamine and iminium catalysis are typical yet powerful organocatalysts to promote metal-free chemical transformations. Since these reactions are generally restricted to twoelectron pathways, equivalent to polarity-driven reactions, they have recently been used in elegant merging examples with photoredox catalysis, namely, one-electron pathways, equivalent to radical-driven reactions. As discussed in this Review, we believe that the key to develop new reactions in this realm would be a formal understanding of the reaction mechanisms. In order to take advantage of open shell reactivity, one must consider SET processes, which should be described formally. In the field of iminium catalysis, Melchiorre recently performed a challenging study to realize effective radical conjugate additions (Scheme 89).231,232 More specifically, α,β-unsaturated carbon-

reactivity was formally localized at the carbazole ring. Although undesired back electron transfer was possible, the relatively long-lived aromatic radical cation was also designed to tautomerize to the corresponding imine (125), which is generally known to be favorable in this equilibrium. At this step, the imine (125·+) with a relatively long-lived aromatic radical cation was obtained and one-electron reduction gave the neutral form (125), which was then simply hydrolyzed to afford the desired products (126). Here, the molecular structures were elegantly designed to maximize the potentials of both organocatalysis and photoredox catalysis, which was rationally understood from our formalism. In particular, the intramolecular SET was the key to regulating the distinctive and unique radical cation reactivity.

Scheme 89. Iminium Ion Trapping by Radicals based on Electron-Relay Electron Relay

Classical formalisms may not have significant scientific meaning in the most current chemical research. We agree that computational approaches based on quantum chemistry must be given appropriate attention in various chemistry research fields. Even so, in this Review, we have attempted to modernize a classical formalism in the realm of synthetic organic chemistry, since we believe it still has potential. Synthetic organic chemists are armed with a wealth of catalysts, including transition metals and their complexes, organocatalysts, Lewis acids and bases, protons, and electrons. A promising next step is to create novel reactivity space by merging these traditional catalysis methods with redox catalysis. In this context, dual or triple catalysis must be compatible with each other. Current redox catalysis, particularly involving photocatalysts, has proven to be the most versatile component. Additionally, recent significant advancements in organic electrochemistry should find further applications in this field, as already demonstrated by Boydston233,234 and Brown.235,236 All of these novel reactivities commonly involve SET processes, where formal understanding of the mechanisms is a practical yet powerful means to explain and/or predict synthetic outcomes. Elusive intramolecular SET processes are also interpreted in unique and novel ways by emphasizing this formalism, which we believe will lead to further reaction developments involving radical-driven mechanisms. Although we have omitted hydrogen atom transfer (HAT) mechanisms from this Review, in addition to protons and electrons, they have also proven to be distinctive catalysts in recent years. Transition metals and their complexes, organocatalysts, Lewis acids and bases will definitely garner continued attention in synthetic organic chemistry since these wellestablished catalysts have already occupied a significant fraction of current research. However, from the viewpoint of increasing awareness of green sustainable aspects, it is obvious that synthetic organic chemists should place protons, electrons, and hydrogen atoms in their growing toolbox of catalysts. Current multiple catalyzes can also be regarded as the blending of established catalysts in order to regulate and/or promote the action of protons, electrons, and hydrogen atoms, which are inspired by natural photosynthesis. We hope this classical formalism will also be merged with computational approaches based on quantum chemistry to create a novel trend for explaining and understanding the greatly expanding field of synthetic organic chemistry.

8. CONCLUSION

yls (116) are converted to the corresponding iminium cations (119) in the presence of primary amine catalysts, and thus, they are activated for conjugate additions. In this context, neutral radicals can also participate in the conjugate addition. However, the problem is that the formed radical cations (120) are generally highly reactive and the equilibrium in this conjugate addition is usually biased toward the starting iminium cations (Scheme 90). In order to overcome this fundamental issue, Scheme 90. Expected Equilibrium in the Conjugate Radical Addition

Melchiorre introduced a carbazole moiety into the primary amine catalyst (121), which was creatively designed to be located in close proximity to the position where an olefinic radical would form after the conjugate addition (Scheme 91). When the neutral radicals, generated by photochemical SET, were trapped by the iminium cation (122), the corresponding highly reactive radical cation (123) formed. At this step, the nearby electron-rich, redox active carbazole functioned as an effective electron donor to reduce the formed olefinic radical immediately by a rapid intramolecular SET process, converting it to the corresponding enamine (124). The radical cation AF


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Scheme 91. Proposed Reaction Mechanism of the Electron Relay Strategy

AUTHOR INFORMATION

working with Professor Kevin D. Moeller, he was promoted to Full Professor in 2004.

Corresponding Author

*E-mail: [email protected].

ACKNOWLEDGMENTS The authors are supported by JSPS KAKENHI Grants 15H04494 and 17K19222 (to K.C.) and 16H06193 and 17K19221 (to Y.O.).

ORCID

Yohei Okada: 0000-0002-4353-1595 Kazuhiro Chiba: 0000-0002-9580-5236 Notes

REFERENCES

The authors declare no competing financial interest.

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Biographies Yohei Okada has been on the faculty at Tokyo University of Agriculture and Technology since 2014. He was born in 1984 in Tokyo, Japan, and received his undergraduate degree at Tokyo University of Agriculture and Technology in 2007. He received his M.S. in 2009 and Ph.D. in 2011, respectively, from the same institution under the direction of Professor Kazuhiro Chiba. After completing a postdoctoral fellowship at Stanford University studying with Professor Eric T. Kool, he returned to Tokyo University of Agriculture and Technology as an Assistant Professor in 2014. Kazuhiro Chiba has been on the faculty at Tokyo University of Agriculture and Technology since 1990. He was born in 1959 in Tokyo, Japan, and received his undergraduate degree at Tokyo University of Agriculture and Technology in 1981. He received his M.S. in 1983 from the same institution under the direction of Professor Masahiro Tada, after which he joined the Kewpie Corporation. In 1990, he returned to Tokyo University of Agriculture and Technology as a Research Associate and received his Ph.D. in 1991 from the same institution studying with Professor Masahiro Tada. He was promoted to Associate Professor in 1996, and after a stay at Washington University in St. Louis as a visiting researcher AG


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